2-Substituted-isoindoles: A novel synthetic route and a study of the iels-Alder and Michael reactions

Article abstract of DOI:10.3184/174751911X13179842027190

A novel one-step procedure for the synthesis of 2-substituted-isoindoles and 1-aryl-2-substituted-isoindoles is described. The procedure is based on the reaction of 2-(bromomethyl)benzaldehyde or 2-(bromomethyl)benzophenone derivatives with primary aromatic or aliphatic amines. Reactions of 1,2-diarylisoindoles with N-phenylmaleimide were studied. Refluxing the reactants in i-PrOH in the presence of triethylamine leads to the formation of Diels-Alder endo-adducts; whilst refluxing in AcOH in the presence of AcONa affords Michael adducts. The structure of the latter was confirmed by X-ray diffraction.

Full text of DOI:10.3184/174751911X13179842027190

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 615
NOVEMBER, 615–618
2-Substituted-isoindoles: a novel synthetic route and a study of the
Diels–Alder and Michael reactions
Zoia V. Voitenkoa, Volodymyr V. Sypchenkoa, Igor V. Levkova*, Lyudmila M. Potikhaa,
Volodymyr A. Kovtunenkoa, Oleg V. Shishkinb and Svetlana V. Shishkinab
aKiev NationalTaras Shevchenko University, 64 Str Volodymyrs’ka, 01033 Kiev, Ukraine
bSTC “Institute of Single Crystals” NASU, 60 Lenina ave, 61001 Kharkiv, Ukraine
A novel one-step procedure for the synthesis of 2-substituted-isoindoles and 1-aryl-2-substituted-isoindoles is
described. The procedure is based on the reaction of 2-(bromomethyl)benzaldehyde or 2-(bromomethyl)benzophen-
one derivatives with primary aromatic or aliphatic amines. Reactions of 1,2-diarylisoindoles with N-phenylmaleimide
were studied. Refluxing the reactants in i-PrOH in the presence of triethylamine leads to the formation of Diels–Alder
endo-adducts; whilst refluxing in AcOH in the presence of AcONa affords Michael adducts. The structure of the latter
was confirmed by X-ray diffraction.
Keywords: isoindoles, maleimides, cycloadditions, benzophenone, Diels–Alder and Michael reactions
The chemistry of isoindole and its derivatives is a rather young
field in the chemistry of heterocyclic compounds.1 At the same
time, the amount of published papers devoted to research
in this sphere is constantly growing. The cause of the high
interest by researchers is not only due to the peculiar structure
and properties of these compounds, but also their availability
for practical applications. Thus, various heat-resistant and
current-conductive polymers,2 dyes3,4 and materials with
non-linear optical properties based on isoindole derivatives
have been synthesised.5 The derivatives of isoindole have
a wide spectrum of biological activity.6–8 2-Substituted-
isoindoles possess valuable properties as CNS-stimulants,
as antidepressants and hypotensive agents, but, especially
1-aryl-2-substituted-isoindoles, are quite difficult to obtain.
Several methods for the synthesis of 1-aryl-2-substituted-
isoindoles have been developed and reported that include,
the action of organometallic compounds on phthalimidine9,10
and reduction of fused isoindoles with lithium aluminum
hydride.11,12
The structure of the compounds 3a–h was determined by
elemental analysis and spectral data. The chemical shift of the
1
H-3 proton in the H NMR spectra of the compounds 3a–h
depends on the nature of the substituent at N(2). Thus, when
R1 = alkyl, δ H-3 (H-3 and H-1 for 3a) = 7.3–7.4 ppm. How-
ever, when R1 = aryl, the signal was deshielded δ H-3 (H-3 and
H-1 for 3b) = 7.4–7.6 ppm. Signals for the protons H-4–H-7
appeared as two multiplets within the ranges 7.32–7.54 ppm
and 6.81–6.93 ppm.
In the UV spectra of the 1,2-diarylisoindoles 3c-f three
distinct absorption bands are observed at λ = 220–260, 270–
310 and 320–370 nm, while the 1-aryl-2-alkyl-isoindoles 3g,h
have only two bands at λ = 210–250 and 320–370 nm. The
presence of the long-wave absorption band at 320–370 nm is a
characteristic peculiarity of isoindole derivatives and is caused
by the presence of the o-quinonoid chromophore.18 Thus, the
UV spectral data confirms the structure of compounds 3a–h as
derivatives of isoindole.
The presence of the diene fragment in the structure of the
isoindoles enables [4+2]-cycloaddition reactions to be carried
out. N-Phenylmaleimide was chosen as the active dienophile.
The outcome of the reaction of the 1,2-diarylisoindoles
3c,3e and 3f with N-phenylmaleimide 4 depends on the
reaction conditions. In the first case the reaction mixture was
kept under reflux in isopropanol during 5 hours (Scheme 2).
Under these conditions the major product was the Diels–Alder
adducts 5c, 5e and 5f. The products were all obtained as the
endo-isomers, which was confirmed by 1H NMR spectral data,
using criteria described in literature.19,20 The signals of the
Results and discussion
In elaboration of our studies of isoindole chemistry,13 we have
developed a convenient one-step method for the synthesis of
2-substituted-isoindoles and 1-aryl-2-substituted-isoindoles,
based on the reaction of the derivatives of 2-(bromomethyl)be
nzaldehyde14 1a and 2-(bromomethyl)benzophenone15 1b with
primary aromatic and aliphatic amines (Table 1).
2-(Bromomethyl)benzaldehyde 1a and 2-(bromomethyl)be
nzophenone 1b have been known for a long time, but have
not been used extensively in heterocyclisations due to their
relative inaccessibility and instability. However, improved
procedures to access 1a and 1b are available.14,15 The reactivity
of these bifunctional systems towards amines was therefore
investigated.
Table 1 Synthesis of 2-substituted-isoindoles and 1-aryl-2-
substituted-isoindoles
The reaction of the 2-(bromomethyl)benzaldehyde 1a with
benzylamine or p-phenetidine proceeded smoothly and resulted
in the formation of the 2-substituted-2H-isoindoles 3a and 3b
respectively in high yields (73 and 88%). The best results were
obtained under an inert atmosphere in 95% ethanol at room
temperature with a twofold excess of the amine. Melting points
and spectral properties of the obtained isoindole 3a conform
with the literature.16,17 The reaction of the 2-(bromomethyl)ben
zophenone 1b with amines required heating for 3 hours at
50 °C, and the reaction can also be carried out without an inert
atmosphere.
Entry
R1
R2
2
3
Yield/%
1
2
3
4
5
6
7
8
H
H
Bn
4-EtOC6H4
4-EtOC6H4
2a
2b
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
88
73
68
64
55
64
67
41
4-ClC6H4
4-ClC6H4 3,4-(MeO)2C6H3
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
Cy
3g
3h
Bn
2a
* Correspondent. E-mail: levkov.igor@gmail.com

616 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1 The Diels–Alder reaction of 1,2-diarylisoindoles
3c,e,f with N-phenylmaleimide.
aliphatic protons, that form the AMX spin system in the
1H NMR spectra appeared within the range 3.80–5.80 ppm
(Table 2).
All attempts to obtain the exo-isomer of 5, which is thermo-
dynamically more stable, turned out to be unsuccessful. Upon
heating in high-boiling solvents, a retro-Diels–Alder reaction
occurred and the endo-adduct decomposed with the formation
of the parent isoindole and N-phenylmaleimide.
Fig. 1 The molecular structure of the molecule 6f with atomic
When a mixture of 3c, 3e or 3f and N-phenylmaleimide was
heated under reflux in acetic acid with a catalytic amount of
sodium acetate during 5 hours (Scheme 3). The products from
this procedure were the Michael adducts 6c, 6e and 6f. In this
case, the aliphatic proton signals appeared as typical ABX spin
numbering used in structural analysis.
According to the X-ray diffraction study, the bicyclic frag-
ment of the molecule 6f is planar within 0.01 Å. The presence
of bulky vicinal substituents causes significant steric strain in
the molecule (shortened intramolecular contacts H3…C24
2.76 Å and H21…C15 2.56 Å, van der Waals radii sum21
2.87 Å). This leads to deviation of the substituent at the C1
atom from the plane of the bicyclic fragment [the C21–C1–
C2–C3 torsion angle is 10.7(8)°] and non-coplanarity of the
π-system of substituents at the C8 and N1 atoms and bicyclic
fragment [the C7–C8–C9–C10 and C1–N1–C15–C16 torsion
angles are –49.5(6)° and 94.9(5)°, respectively]. The
pyrrolidinedione ring adopts an envelope conformation with
deviation of the C21 atom by 0.13 Å from the mean plane of
the remaining ring atoms and is turned in such way that the
C21–C22 bond has +sc–orientation relative to the C2–C1 bond
of the bicyclic fragment [the C2–C1–C21–C22 torsion angle
is 72.7(6)°]. The phenyl substituent is twisted relative to the
pyrrolidinedione ring (the C24–N2–C25–C26 torsion angle is
–47.7(6)°).
1
systems in their H NMR spectra that absorbed within the
range 2.90–4.70 ppm (Table 3).
The diene fragment is also present in compounds 6c, 6e
and 6f, but we failed to isolate any of the Diels–Alder adduct
with one more molecule of N-phenylmaleimide, this failure is
probably caused by steric hindrance.
The structure of the product 6f was identified not only
by spectral methods but also by X-ray diffraction analysis
(Fig. 1).
Table 2 The characteristic 1H NMR signals of Diels–Alder
adducts 5c, 5e and 5f. The chemical shifts of 5e and 5f are
reported in the experimental section
Compound
δ/ppm
J/Hz
5c
Ha 3.85 dd
Hm 4.50 d
Hx 5.64 d
JHaHm = 8.2 Hz, JHaHx = 7.3 Hz
JHaHm = 8.2 Hz
JHaHx = 7.3 Hz
In conclusion, the reaction of 2-(bromomethyl)benzaldehyde
or 2-(bromomethyl)benzophenone with primary amines leads
to the formation of 2-substituted-2H-isoindoles. It is demon-
strated that the reaction of 1,2-diarylisoindoles with N-phenyl-
maleimide can result in the formation of either Diels–Alder of
Michael adducts, depending on the reaction conditions.
Experimental
IR spectra were obtained with a Perkin-Elmer Spectrum BX
1
spectrometer. H and 13C NMR spectra were recorded with a Varian
Mercury 400 (400 and 100 MHz, respectively) spectrometer using
tetramethylsilane as the internal standard. UV absorption spectra were
recorded with a UV-Vis Spectrometer Lambda 20. Melting points
were determined on a Boetius apparatus and are uncorrected. Elemen-
tal analyses were carried out with a Vario MICRO Cube elemental
analyser.2-(Bromomethyl)benzaldehyde 1a14 and 2-(bromomethyl)
phenyl](4-chlorophenyl)methanone 1b15 were prepared as described
previously in the literature.
2-Benzyl-2H-isoindole (3a): To the solution of benzylamine (1.07 g,
10.0 mmol) in ethanol (10 mL) under an inert atmosphere with
intensive stirring was added dropwise a solution of 2-(bromomethyl)
benzaldehyde 1a (1.0 g, 5.0 mmol) in ethanol (4 mL). The reaction
mixture was stirred for 2 h at r.t. and the precipitate formed was
filtered and washed with the minimal quantity of cold ethanol.
Yield 0.91 g (88%); pale yellow solid; m.p. 113–116 °C (lit.16 m.p.
Scheme 2 The Michael reaction of 1,2-diarylisoindoles 3c, 3e
and 3f with N-phenylmaleimide.
Table 3 The characteristic proton signals of Michael adducts
6c, 6e, and 6f in 1H NMR spectra. The chemical shifts of 6e,f are
reported in the experimental section
Compound
δ/ppm
J/Hz
6c
Ha 2.97 dd
Hb 3.26 dd
Hx 4.67 dd
JHaHb = 17.0 Hz, JHaHx = 8.0 Hz
JHaHb = 17.0 Hz, JHbHx = 10.0 Hz
JHaHx = 8.0 Hz, JHbHx = 10.0 Hz

JOURNAL OF CHEMICAL RESEARCH 2011 617
111–118 °C). IR (KBr) (νmax, cm−1): 3106, 3028, 1713, 1602, 1494,
1455, 1432, 1362, 1323, 1152, 1137, 763, 747 . 1H NMR (400 MHz,
DMSO-d6/CCl4): δ = 5.42 (s, 2 H, CH2), 6.81 (m, 2 H, 5-H, 6-H),
7.22–7.38 (m, 7 H, ArH), 7.45 (m, 2 H, 4-H, 7-H) ppm. 13C NMR
(100 MHz, DMSO-d6/CCl4): δ = 53.7, 110.9, 119.4, 119.9, 123.9,
127.3, 127.5, 128.4, 138.0 ppm. UV (MeOH): λmax (log ε) = 224 (4.47),
327 (3.49) nm. Anal. Calcd for C15H13N: C, 86.92; H, 6.32; N, 6.76.
Found: C, 86.67; H, 6.36; N, 6.81%.
for C20H13ClFN: C, 74.65; H, 4.07; N, 4.35. Found: C, 74.83; H, 4.08;
N, 4.30%.
1-(4-Chlorophenyl)-2-cyclohexyl-2H-isoindole (3g): Yield 0.67 g
(67%); white solid; m.p. 112–114 °C. IR (KBr) (νmax, cm−1): 3053,
2924, 2852, 1524, 1491, 1446, 1337, 1155, 1085, 1013, 825, 747.
1H NMR (400 MHz, DMSO-d6/CCl4): δ = 1.32 (m, 3 H, Alk-H), 1.69
(m, 1 H, Alk-H), 1.84 (m, 4 H, Alk-H), 2.00 (m, 2 H, Alk-H), 4.23
(m, 1 H, NCH(CH2-)2), 6.81 (m, 2 H, 5-H, 6-H), 7.32 (d, J = 8.0 Hz,
1 H, 4(7)-H), 7.36–7.46 (m, 4 H, 3-H, 7(4)-H, 3′-H, 5′-H), 7.48 (d,
J = 8.0 Hz, 2 H, 2′-H, 6′-H) ppm. 13C NMR (100 MHz, DMSO-
d6/CCl4): δ = 25.3, 25.9, 35.1, 56.4, 108.9, 119.0, 119.9, 120.7, 120.9,
121.2, 122.7, 123.9, 129.2, 130.9, 131.6, 132.2 ppm. UV (MeOH):
λmax (log ε) = 236 (4.46), 356 (3.85) nm. Anal. Calcd for C20H20ClN:
C, 77.53; H, 6.51; N, 4.52. Found: C, 77.59; H, 6.48; N, 4.57%.
2-Benzyl-1-(4-chlorophenyl)-2H-isoindole (3h): Yield 0.42 g (41%);
yellow solid; m.p. 101–103 °C. IR (KBr) (νmax, cm−1): 3048, 1522,
1494, 1449, 1415, 1357, 1340, 1214, 1161, 1088, 1010, 831, 750.
1H NMR (400 MHz, DMSO-d6/CCl4): δ = 5.45 (s, 2 H, CH2), 6.85 (m,
2 H, 5-H, 6-H), 6.92 (d, J = 7.2 Hz , 2 H, 2″-H, 6″-H), 7.15–7.24 (m,
3 H, 3″-H, 4″-H, 5″-H), 7.33 (s, 1 H, 3-H), 7.35-7.47 (m, 6 H, ArH)
ppm. 13C NMR (100 MHz, DMSO-d6/CCl4): δ = 51.7, 113.5, 119.2,
120.0, 121.3, 121.6, 121.7, 123.4, 123.9, 126.8, 127.7, 128.9, 129.0,
130.7, 131.4, 132.3, 138.3 ppm. UV (MeOH): λmax (log ε) = 220 (4.45),
358 (3.88) nm. Anal. Calcd for C21H16ClN: C, 79.36; H, 5.07; N, 4.41.
Found: C, 79.03; H, 5.15; N 4.39%.
2-(4-Ethoxyphenyl)-2H-isoindole (3b): Prepared according to the
procedure outline for 3a with the use of 4-ethoxyaniline 2b, (1.37 g,
10.0 mmol) and 2-(bromomethyl)benzaldehyde (1a, 1.0 g, 5.0 mmol).
Yield 0.87 g (73%); white solid; m.p. 168–170 °C. IR (KBr) (νmax
,
cm−1): 3121, 3054, 2980, 2930, 1517, 1476, 1396, 1251, 1184, 1117,
1052, 923, 825, 758. 1H NMR (400 MHz, DMSO-d6/CCl4): δ = 1.40
(t, J = 7.2 Hz, 3 H, CH3), 4.08 (q, J = 7.2 Hz, 2 H, CH2), 6.85 (m, 2 H,
5-H, 6-H), 7.04 (d, J = 9.0 Hz, 2 H, 3′-H, 5′-H), 7.49 (m, 2 H, 4-H,
7-H), 7.61 (m, 4 H, 1-H, 3-H, 2′-H, 6′-H) ppm. 13C NMR (100 MHz,
DMSO-d6/CCl4): δ = 14.7, 63.3, 109.4, 115.2, 119.6, 120.7, 122.5,
124.7, 133.3, 157.3 ppm. UV (MeOH): λmax (log ε) = 214 (4.41), 247
(4.37), 297 (4.02), 331 (3.60) nm.Anal. Calcd for C16H15NO: C, 80.98;
H, 6.37; N, 5.90. Found: C, 80.76; H, 6.39; N, 5.88%.
Synthesis of 1-aryl-2-substituted-2H-isoindoles 3c–h; general proce-
dure
To a solution of the appropriate amine 2a–f (6.46 mmol) in isopropa-
nol (15 mL) was added 2-bromomethyl-4′-chlorobenzophenone 1b
(1.0 g, 3.23 mmol). The reaction mixture was heated for 3 hours at
50 °C, and after cooling the precipitate formed was filtered and
washed with isopropanol.
Synthesis of Diels–Alder adducts 5c,5e and 5f; general procedure
A mixture of the isoindole 3c, 3e or 3f (0.5 mmol) and N-phenylma-
leimide 4 (86.5 mg, 0.5 mmol) was kept under reflux for 5 hours in
isopropanol (10 mL) containing triethylamine (1 mL). After cooling
the precipitate was filtered and washed with isopropanol.
Diels–Alder adduct (5c): Yield 0.15 g (57%); light yellow solid;
m.p. 169–170 °C. IR (KBr) (νmax, cm−1): 3060, 3032, 2968, 2900,
2866, 1694, 1494, 1372, 1226, 1172, 1042, 822, 744. 1H NMR
(400 MHz, DMSO-d6/CCl4): δ = 1.33 (t, J = 7.2 Hz, 3 H), 3.85 (dd,
J = 7.3, 8.2 Hz, 1 H), 3.91 (q, J = 7.2 Hz, 2 H), 4.50 (d, J = 8.2 Hz,
1 H), 5.64 (d, J = 7.3 Hz, 1 H), 6.41 (m, 2 H), 6.66 (m, 5 H), 7.25–7.35
(m, 5 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.84 (d,
J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, DMSO-d6/CCl4): δ = 15.2,
49.5, 49.8, 63.5, 68.3, 79.0, 115.2, 121.4, 121.5, 121.9, 127.1, 128.0,
128.2, 128.8, 129.1, 129.4, 131.0, 132.1, 133.5, 136.0, 138.3, 140.1,
146.2, 154.1, 174.5, 175.0 ppm. Anal. Calcd for C32H25ClN2O3: C,
73.77; H, 4.84; N, 5.38. Found: C, 73.52; H, 4.77; N, 5.39%.
Diels–Alder adduct (5e): Yield 0.20 g (72%); light yellow solid;
m.p. 175–176 °C. IR (KBr) (νmax, cm−1): 3058, 3042, 2998, 2956,
1700, 1472, 1364, 1166, 758, 740. 1H NMR (400 MHz, DMSO-
d6/CCl4): δ = 3.85 (dd, J = 7.3, 8.2 Hz, 1 H), 4.50 (d, J = 8.2 Hz, 1 H),
5.80 (d, J = 7.3 Hz, 1 H), 6.39 (m, 2 H), 6.61 (d, J = 7.6 Hz, 1 H), 6.72
(d, J = 8.8 Hz, 2 H), 7.22–7.27 (m, 6 H), 7.31 (t, J = 7.2 Hz, 1 H), 7.41
(d, J = 7.2 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.84 (d, J = 8.4 Hz,
2 H) ppm. 13C NMR (100 MHz, DMSO-d6/CCl4): δ = 49.0, 49.9, 67.8,
78.8, 114.3, 121.5, 121.9, 122.1, 127.1, 128.2, 128.3, 128.9, 129.1,
129.6, 130.9, 132.0, 132.1, 133.7, 135.6, 139.6, 144.6, 146.1, 174.2,
174.7 ppm. Anal. Calcd for C30H20BrClN2O2: C, 64.82; H, 3.63; N,
5.04. Found: C, 65.12; H, 3.57; N 5.13%.
1-(4-Chlorophenyl)-2-(4-ethoxyphenyl)-2H-isoindole (3c): Yield
0.76 g (68%); white solid; m.p. 162–164 °C. IR (KBr) (νmax, cm−1):
3109, 2980, 2919, 1589, 1513, 1494, 1471, 1245, 1091, 1041, 836,
1
820, 758, 750. H NMR (400 MHz, DMSO-d6/CCl4)22: δ = 1.41 (t,
J = 7.2 Hz, 3 H, CH3), 4.05 (q, J = 7.2 Hz, 2 H, CH2), 6.92 (m, 4 H,
5-H, 6-H, 3″-H, 5″-H), 7.18 (m, 4 H, 3′-H, 5′-H, 2″-H, 6″-H), 7.29 (d,
J = 8.0 Hz, 2 H, 2′-H, 6′-H), 7.41 (s, 1 H, H-3), 7.54 (m, 2 H, 4-H, 7-H)
ppm. 13C NMR (100 MHz, DMSO-d6/CCl4): δ = 15.0, 63.6, 114.9,
115.1, 119.2, 120.2, 121.2, 121.8, 122.4, 123.6, 124.4, 127.5, 128.6,
130.9, 131.3, 132.7, 158.3 ppm. UV (MeOH): λmax (log ε) = 226 (4.49),
290 (4.15), 360 (3.92) nm. Anal. Calcd for C22H18ClNO: C, 75.97; H,
5.22; N, 4.03. Found: C, 75.89; H, 5.18; N, 4.06%.
1-(4-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-2H-isoindole (3d):
Yield 0.75 g (64%); white solid; m.p. 158–160 °C. IR (KBr) (νmax
,
cm−1): 3075, 2941, 2835, 1597, 1519, 1494, 1443, 1256, 1236, 1169,
1
1130, 1080, 1021, 831, 811, 747. H NMR (400 MHz, DMSO-d6/
CCl4): δ = 3.65 (s, 3 H, 4″-OCH3), 3.80 (s, 3 H, 3″-OCH3), 6.75 (d,
J = 8.0 Hz, 1 H, 6″-H), 6.86–6.94 (m, 4 H, 5-H, 6-H, 2″-H, 5″-H), 7.19
(d, J = 8.0 Hz, 2 H, 3′-H, 5′-H), 7.30 (d, J = 8.0 Hz, 2 H, 2′-H, 6′-H),
7.46 (s, 1 H, 3-H), 7.53 (m, 2 H, 4-H, 7-H) ppm. 13C NMR (100 MHz,
DMSO-d6/CCl4): δ = 56.1, 56.2, 110.9, 112.0, 115.2, 118.6, 119.5,
120.4, 121.4, 122.1, 122.7, 123.9, 124.6, 128.9, 131.2, 131.3, 131.6,
133.2, 149.0, 149.5 ppm. UV (MeOH): λmax (log ε) = 232 (4.49), 298
(4.16), 360 (3.91) nm. Anal. Calcd for C22H18ClNO2: C, 72.62; H,
4.99; N, 3.85. Found: C, 72.97; H, 5.04; N 3.79%.
2-(4-Bromophenyl)-1-(4-chlorophenyl)-2H-isoindole (3e): Yield
0.68 g (55%); slightly yellow solid; m.p. 153–155 °C. IR (KBr) (νmax
,
Diels–Alder adduct (5f): Yield 0.16 g (65%); light yellow solid;
cm−1): 3064, 1491, 1399, 1348, 1320, 1194, 1088, 1066, 1013, 834,
m.p. 148–149 °C. IR (KBr) (νmax, cm−1): 3056, 2962, 1700, 1492,
1
1
755. H NMR (400 MHz, DMSO-d6/CCl4): δ = 6.93 (m, 2 H, 5-H,
1360, 1208, 1162, 832, 740. H NMR (400 MHz, DMSO-d6/CCl4):
6-H), 7.12–7.24 (m, 4 H, 2″-H, 6″-H, 3′-H, 5′-H), 7.30 (d, J = 8.0 Hz,
2 H, 2′-H, 6′-H), 7.46 (s, 1 H, 3-H), 7.54 (m, 4 H, 4-H, 7-H, 3″-H,
5″-H) ppm. 13C NMR (100 MHz, DMSO-d6/CCl4): δ = 114.8, 119.3,
120.3, 121.1, 121.3, 122.2, 122.8, 124.1, 124.7, 128.3, 128.8, 130.4,
131.0, 131.7, 132.5, 139.2 ppm. UV (MeOH): λmax (log ε) = 241 (4.48),
280 (4.17), 357 (3.97) nm. Anal. Calcd for C20H13BrClN: C, 62.77; H,
3.42; N, 3.66. Found: C, 63.15; H, 3.51; N, 3.59%.
1-(4-Chlorophenyl)-2-(4-fluorophenyl)-2H-isoindole (3f): Yield
0.67 g (64%); white solid; m.p. 121–123 °C. IR (KBr) (νmax, cm−1):
3070, 1510, 1494, 1214, 1197, 1088, 839, 822, 755. 1H NMR
(400 MHz, DMSO-d6/CCl4): δ = 6.93 (m, 2 H, 5-H, 6-H), 7.10–7.22
(m, 4 H, 3′-H, 5′-H, 3″-H, 5″-H), 7.28 (m, 4 H, 2′-H, 6′-H, 2″-H, 6″-
H), 7.45 (s, 1 H, 3-H), 7.54 (m, 2 H, 4-H, 7-H) ppm. 13C NMR
(100 MHz, DMSO-d6/CCl4): δ = 115.2, 116.7 (d, J = 22 Hz), 119.5,
120.5, 121.6, 122.3, 122.9, 124.1, 124.8, 128.7 (d, J = 9 Hz), 129.0,
130.8, 131.3, 131.9, 136.5, 161.9 (d, J = 245 Hz) ppm. UV (MeOH):
λmax (log ε) = 244 (4.50), 288 (4.16), 360 (4.03) nm. Anal. Calcd
δ = 3.85 (dd, J = 7.3, 8.2 Hz, 1 H), 4.50 (d, J = 8.2 Hz, 1 H), 5.73
(d, J = 7.3 Hz, 1 H), 6.40 (m, 2 H), 6.64 (d, J = 7.2 Hz, 1 H), 6.77 (m,
2 H), 6.89 (t, J = 8.4 Hz, 2 H), 7.26 (m, 4 H), 7.33 (t, J = 7.2 Hz, 1 H),
7.41 (d, J = 7.2 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.83 (d, J = 8.4 Hz,
2 H) ppm. 13C NMR (100 MHz, DMSO-d6/CCl4): δ = 49.3, 49.8, 68.2,
79.0, 115.9 (d, J = 22 Hz), 121.6, 121.7 (d, J = 9 Hz), 121.9, 127.1,
128.1, 128.3, 128.8, 129.1, 129.5, 130.9, 132.0, 133.7, 135.7, 139.9,
141.6, 146.0, 157.9 (d, J = 245 Hz), 174.3, 174.8 ppm. Anal. Calcd for
C30H20ClFN2O2: C, 72.80; H, 4.07; N, 5.66. Found: C, 72.73; H, 4.15;
N, 5.51%.
Synthesis of Michael adducts 6c, 6e and 6f: general procedure
A mixture of of isoindole 3c, 3e or 3f (0.5 mmol) and N-phenylma-
leimide 4 (86.5 mg, 0.5 mmol) was kept under reflux for 5 hours
in acetic acid (10 mL) containing anhydrous sodium acetate (1 mg).
After cooling the precipitate was filtered and washed with
isopropanol.

618 JOURNAL OF CHEMICAL RESEARCH 2011
Michael adduct (6c): Yield 0.19 g (73%); red solid; m.p. 253–
254 °C. IR (KBr) (νmax, cm−1): 3062, 2982, 2940, 2888, 1708, 1512,
1498, 1386, 1248, 1180, 754, 698. 1H NMR (400 MHz, DMSO-
d6/CCl4): δ = 1.41 (t, J = 7.2 Hz, 3 H), 2.97 (dd, J = 8.0, 17.0 Hz, 1 H),
3.26 (dd, J = 10.0, 17.0 Hz, 1 H), 4.03 (q, J = 7.2 Hz, 2 H), 4.67 (dd,
J = 8.0, 10.0 Hz, 1 H), 6.93–7.00 (m, 4 H), 7.19 (m, 5 H), 7.26 (d,
J = 7.2 Hz, 2 H), 7.41–7.48 (m, 5 H), 7.56 (d, J = 7.2 Hz, 1 H) ppm.
13C NMR (100 MHz, DMSO-d6/CCl4): δ = 15.2, 37.0, 38.7, 63.5,
117.7, 120.0, 120.7, 122.2, 122.7, 122.9, 123.2, 123.3, 127.5, 128.9,
129.1, 129.4, 130.6, 131.5, 131.7, 132.8, 132.9, 133.2, 140.1, 175.2,
176.5 ppm. Anal. Calcd for C32H25ClN2O3: C, 73.77; H, 4.84; N, 5.38.
Found: C, 74.03; H, 4.72; N, 5.41%.
coordinates, and crystallographic data for molecule 6f have been
deposited with the Cambridge Crystallographic Data Centre, 12 Union
Road CB2 1EZ, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.
cam.ac.uk) and are available on request quoting the deposition
numbers CCDC. CCDC-821341 (for 6f) contains the supplementary
crystallographic data for this paper.
Received 16 August 2011; accepted 5 October 2011
Paper 1100845 doi: 10.3184/174751911X13179842027190
Published online: 22 November 2011
References
Michael adduct (6e): Yield 0.23 g (82%); red solid; m.p. 250–
251 °C. IR (KBr) (νmax, cm−1): 3064, 2924, 1712, 1496, 1380, 1184,
1
2
3
F.S. Babichev, V.A. Kovtunenko and A.K. Tyltin, Russ. Chem. Rev., 1981,
50, 1087.
Y.S. Lee, H.S.-W. Hu and O.-K. Kim, Mol. Cryst. Liq. Cryst., 1990, 190,
9.
Z.V. Voitenko, T.V. Yegorova, V.A. Kovtunenko, R.I. Zubatyuk, S.V.
Shishkina, O.V. Shishkin, M.D. Tsapko and A.V. Turov, J. Mol. Struct.,
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1
1012, 752, 692. H NMR (400 MHz, DMSO-d6/CCl4): δ = 3.03 (dd,
J = 8.0, 17.0 Hz, 1 H), 3.29 (dd, J = 10.0, 17.0 Hz, 1 H), 4.63 (dd,
J = 8.0, 10.0 Hz, 1 H), 6.99 (m, 2 H), 7.01–7.70 (m, 15 H) ppm. 13
C
NMR (100 MHz, DMSO-d6/CCl4): δ = 37.1, 38.7, 118.8, 119.8, 120.6,
122.2, 122.8, 122.9, 123.1, 123.2, 127.4, 128.9, 129.0, 129.4, 130.5,
131.6, 131.8, 132.8, 132.9, 133.0, 136.9, 175.2, 176.5 ppm. Anal.
Calcd for C30H20BrClN2O2: C, 64.82; H, 3.63; N, 5.04. Found: C,
64.93; H, 3.54; N, 5.13%.
4
5
Z.V. Voitenko, A.I. Kysil’ and J.G. Wolf, Dyes Pigm., 2007, 74, 477.
G.Y. Yang, M. Hanack, Y.W. Lee, Y. Chen, M.K.Y. Lee and D. Dini, Chem.
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6
J.R. Colca, S.D. Larsen, M.D. Meglasson and S.P. Tanis, PCT Int. Appl.
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Michael adduct (6f): Yield 0.19 g (77%); red solid; m.p. 254–255
°C. IR (KBr) (νmax, cm−1): 3060, 2968, 2916, 2840, 1704, 1496, 1364,
7
8
1
1212, 1168, 1076, 860, 748, 736, 696. H NMR (400 MHz, DMSO-
d6/CCl4): δ = 3.00 (dd, J = 8.0, 17.0 Hz, 1 H), 3.27 (dd, J = 10.0,
17.0 Hz, 1 H), 4.62 (dd, J = 8.0, 10.0 Hz, 1 H), 6.99 (m, 2 H), 7.00–
7.57 (m, 15 H) ppm. 13C NMR (100 MHz, DMSO-d6/CCl4): δ = 37.0,
38.7, 116.8 (d, J = 22 Hz), 118.8, 119.8, 120.7, 122.2, 122.7, 123.1,
123.4, 127.4, 129.0, 129.4, 130.6, 131.6, 131.8 (d, J = 9 Hz), 132.9,
133.9, 162.5 (d, J = 245 Hz), 175.2, 176.6 ppm. Anal. Calcd for
C30H20ClFN2O2: C, 72.80; H, 4.07; N, 5.66. Found: C, 72.54; H, 4.03;
N, 5.51%.
9
W. Theilacker and H. Kalenda, Liebigs Ann. Chem., 1953, 584, 87.
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X-ray crystal structure analysis of 6f: The crystals of 6f
(C30H20N2O2ClF) are orthorhombic. At 293 K a = 23.480(2), b =
9.3059(8), c = 11.296(1) Å, V = 2468.2(4) Å3, Mr = 494.93, Z = 4,
space group Pca21, dcalc = 1.332 g cm−3, µ(MoKα) = 0.193 mm−1, F(000)
= 1024. Intensities of 18624 reflections (4248 independent, Rint =
0.121) were measured on the “Xcalibur-3” diffractometer (graphite
monochromated MoKα radiation, CCD detector, ω-scaning, 2θmax =
50°). The structure was solved by a direct method using the SHELXTL
package.23 Positions of the hydrogen atoms were located from elec-
tron density difference maps and refined by “riding” model with Uiso
= 1.2Ueq of the carrier atom. Full-matrix least-squares refinement
against F2 in anisotropic approximation for non-hydrogen atoms
using 4217 reflections was converged to wR2 = 0.085 (R1 = 0.053
for 2158 reflections with F>4σ(F), S = 0.880). The final atomic
16 T. Ohwada, M. Miura, H. Tanaka, S. Sakamoto, K. Yamaguchi, H. Ikeda
and S. Inagaki, J. Am. Chem. Soc., 2001, 123, 10164.
17 L.A. Carpino, R.E. Padykula, D.E. Barr, F.H. Hall, J.G. Krause, R.F.
Dufresne and C.J. Thoman, J. Org. Chem., 1988, 53, 2565.
18 V.A. Kovtunenko, Z.V. Voitenko, V.L. Sheptun, A.K. Tyltin, A.I. Chernega,
Y.T. Struchkov and F.S. Babichev, Chem. Heterocycl. Compd, 1984, 20,
1235.
19 V.A. Kovtunenko, Z.V.Voitenko,A.K. Tyltin,A.V. Turov and F.S. Babichev,
Ukr. Khim. Zh., 1983, 49, 1287.
20 V.A. Kovtunenko, Z.V. Voitenko, T.T. Kucherenko, A.V. Turov, A.K. Tyltin
and F.S. Babichev, Chem. Heterocycl. Compd, 1990, 26, 161.
21 Yu. V. Zefirov, Kristallografiya 1997, 42, 936.
22 The numbering of the aromatic protons of the aryl substituents for
compounds 3c-h: protons at 1-Ar-H-2′-H-6′; protons at 2-Ar-H-2″-H-6″.
23 G.M. Sheldrick, Acta Crystallogr., A 2008, 64, 112.